Effects of intracellular iron overload on cell death and identification of potent cell death inhibitors
Effects of intracellular iron overload on cell death and identification of potent cell death inhibitors
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细胞内铁过载对细胞死亡的影响和有效细胞死亡抑制剂的鉴定
DOI：
10.1016/j.bbrc.2018.06.019
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发表时间：
2018-09-03
影响因子：
3.1
通讯作者：
Feng, Jie
中科院分区：
文献类型：
--
作者：
Fang, Shenglin;Yu, Xiaonan;Feng, Jie
铁超载导致许多疾病，而这些疾病的潜在病因尚不清楚。细胞死亡过程包括细胞凋亡、坏死性凋亡、亲环素D-（CypD）依赖性坏死和最近描述的称为铁凋亡的另一种形式的调节性细胞死亡，其依赖于铁或铁依赖性活性氧（ROS）。然而，细胞内铁的积累本身是否会诱导铁凋亡或其他形式的细胞死亡在很大程度上是难以捉摸的。本研究分别采用柠檬酸铁铵（FAC）和8-羟基喹啉铁络合物（Fe-8HQ）研究了细胞内铁超载自身诱导的细胞死亡机制。我们发现，FAC-induced细胞内铁超载导致铁凋亡。我们还确定了3-磷酸肌醇依赖性激酶1（PDK 1）抑制剂GSK 2334470作为一种有效的铁凋亡抑制剂。而Fe-8HQ诱导的细胞内铁超负荷导致不受调节的坏死，但部分激活PARP-1依赖的parthanatos。有趣的是，我们确定了许多酚类化合物作为Fe-8HQ诱导的细胞死亡的有效抑制剂。总之，细胞内铁超载诱导的细胞死亡形式可能依赖于细胞内铁积累速率，在我们的研究中新鉴定的细胞死亡抑制剂靶向铁凋亡和不受调节的氧化性细胞死亡代表了针对铁超载相关疾病的潜在治疗策略。(C)2018爱思唯尔公司All rights reserved.
Iron overload causes many diseases, while the underlying etiologies of these diseases are unclear. Cell death processes including apoptosis, necroptosis, cyclophilin D-(CypD)-dependent necrosis and a recently described additional form of regulated cell death called ferroptosis, are dependent on iron or iron-dependent reactive oxygen species (ROS). However, whether the accumulation of intracellular iron itself induces ferroptosis or other forms of cell death is largely elusive. In present study, we study the role of intracellular iron overload itself-induced cell death mechanisms by using ferric ammonium citrate (FAC) and a membrane-permeable Ferric 8-hydroxyquinoline complex (Fe-8HQ) respectively. We show that FAC-induced intracellular iron overload causes ferroptosis. We also identify 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitor GSK2334470 as a potent ferroptosis inhibitor. Whereas, Fe-8HQ-induced intracellular iron overload causes unregulated necrosis, but partially activates PARP-1 dependent parthanatos. Interestingly, we identify many phenolic compounds as potent inhibitors of Fe-8HQ-induced cell death. In conclusion, intracellular iron overload-induced cell death form might be dependent on the intracellular iron accumulation rate, newly identified cell death inhibitors in our study that target ferroptosis and unregulated oxidative cell death represent potential therapeutic strategies against iron overload related diseases. (C) 2018 Elsevier Inc. All rights reserved.